Platelets (thrombocytes), are small anucleate blood cells that are derived from megakaryocytes (MKs) in the bone marrow, spleen and lungs. They are critical mediators of many pathophysiological processes, including thrombosis and haemostasis, immunity and inflammation, cancer and neurodegeneration, however the mechanisms controlling the number and reactivity of platelets in the circulation remain incompletely defined.  Prevailing thinking is that activation signals and mechanical forces are the primary drivers of platelet production (thrombopoiesis) and platelet activation, overlooking the role of inhibitory mechanisms in these processes.

The primary research interest of our group is defining and harnessing the MK/platelet checkpoint, which maintains MKs in a non-thrombopoietic state in sites of platelet production, and platelets in a resting state in the circulation.  This represents a shift from activation-focused models towards inhibitory mechanisms governing when and where MKs produce platelets and how platelets respond to their surroundings.  Central to this model is the co-inhibitory receptor G6b-B, which acts as an intrinsic gatekeeper of this checkpoint, and the extrinsic cues, namely vascular heparan sulfates that bind and regulate the inhibitory activity of G6b-B.  We are also interested in the receptor-type tyrosine phosphatase CD148, which lies upstream of G6b-B and sets the threshold of MK/platelet activation by modulating Src kinase activity.  By understanding how G6b-B and CD148 are regulated by vascular heparan sulfates, synthetic heterobifunctional molecules, in the form of bispecific antibodies can be engineered that harness these receptors and regulate the number and reactivity of platelets in the circulation in disease.

Previous publications

Keywords: platelet homeostasis, megakaryocytes, tyrosine phosphatases and kinases, vascular heparan sulfates, synthetic heterobifunctional molecules, inhibitory receptor G6b-B

Grants

• ANR 2023: TARGITT
• ERC Advanced MENTOR